Clinicopathological Characteristics and Response to Targeted Therapy in Patients with ALKrearranged Non-small-cell Lung Carcinoma harboring TP53 Mutations

Document Type

Conference Proceeding

Publication Date

3-19-2022

Publication Title

Mod Pathol

Abstract

Background: Anaplastic lymphoma kinase (ALK) rearrangements are reported in 3-7% of patients with non-small cell lung carcinoma (NSCLC), where ALK tyrosine kinase inhibitors (ALK-TKIs) have shown to improve progression free survival (PFS) and overall survival (OS). However, most develop resistance post-treatments due to primary and progressive acquired resistance mechanisms. Recent studies have shown that concurrent mutations such as TP53 can affect the prognosis by generating inherent resistance and inferior treatment response. We sought to evaluate the clinicopathological characteristics of patients with ALKrearranged NSCLC and correlate targeted therapy response in patients with/without concurrent TP53 mutations. Design: All NSCLC cases tested for ALK rearrangements over 5.5 years were reviewed. Genomic DNA and RNA were extracted using standard tissue extraction protocols. Fluorescent in situ hybridization (FISH) was performed using a DNA probe cocktail specific for 2p23 chromosome breakpoint. RNA sequencing was performed using Archer Solid Tumor FusionPlex panel that included primers flanking exons 19 through 22 of ALK gene. Targeted DNA NGS panel included TP53 gene covering exons 2, 4-8, 10. All cases fulfilled the NGS and FISH assay acceptability criteria. Results: 23 patients were positive for ALK gene rearrangement, and 7 had concurrent TP53 mutations. Patient characteristics are given in table 1. 5/16 patients with ALK rearranged NSCLC without TP53 mutations developed resistance to first line ALK-TKIs. Median PFS on ALK-TKIs and OS were 12 months (range 1 to 65) and 19 months (range 1 to 87) respectively. 4/7 patients with ALK-rearranged NSCLC with TP53 mutations developed resistance to first line ALK-TKIs. Median PFS on ALK-TKIs and OS was 6 months (range 1 to 38) and 42 months (range 1 to 110) respectively (Figure 1). 15 patients (65%) were alive with disease at the time of review. One tumor underwent small-cell change (patient 11), one squamous change (patient 21), and two acquired progressive mutations in the ALK gene (patients 17 and 18). Conclusions: In our cohort, ALK-rearrangements were predominantly observed in adenocarcinoma in non-smokers in younger age group. Patients with concurrent TP53 mutations had worse PFS with 57% patients manifesting resistance to first line TKIs. Testing for TP53 in patients with ALK-rearranged NSCLC and repeating mutational analysis in case of disease progression on ALK-TKIs may be beneficial in planning treatment options and improving survival.

PubMed ID

Not assigned.

Volume

35

Issue

SUPPL 2

First Page

1323

Last Page

1325

Find It @ Sladen

Share

COinS